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A Phase II Study to Assess the Safety, Tolerability and Efficacy of Xanamem™ in Subjects With Mild Dementia Due to AD (XanADu) (XanADu)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02727699
Recruitment Status : Completed
First Posted : April 5, 2016
Last Update Posted : April 9, 2020
Sponsor:
Collaborator:
ICON Clinical Research
Information provided by (Responsible Party):
Actinogen Medical

Tracking Information
First Submitted Date  ICMJE March 21, 2016
First Posted Date  ICMJE April 5, 2016
Last Update Posted Date April 9, 2020
Actual Study Start Date  ICMJE March 23, 2017
Actual Primary Completion Date March 15, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 8, 2017)
  • ADAS-Cog v14 [ Time Frame: Baseline, Week 12 ]
    Change in Alzheimer's Disease Assessment Scales - Cognitive Subscale Score, version 14 (ADAS-Cog v14)
  • AD COMposite Scores [ Time Frame: Baseline, Week 12 ]
    Change in AD COMposite Scores (ADCOMs, composite data derived from Alzheimer's Disease Assessment Scales - Cognitive Subscale Version 14 [ADAS-Cog v14], Clinical Dementia Rating Scale - Sum of Boxes [CDR-SOB], and Mini-Mental Status Examination [MMSE])
Original Primary Outcome Measures  ICMJE
 (submitted: March 30, 2016)
  • Change in AD COMposite Score (ADCOMs) [ Time Frame: Baseline, Week 4, Week 12 ]
    ADCOMs, composite data derived from three different scales including Alzheimer's Disease Assessment Scales - Cognitive subscale version 14 (ADAS-Cog v14), Clinical Dementia Rating Scale - Sum of Boxes (CDR-SOB), and Mini-Mental Status Examination (MMSE).
  • Change in Alzheimer's Disease Assessment Scales - Cognitive Subscale Score (ADAS-Cog v14) [ Time Frame: Baseline, Week 4, Week 12 ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: November 29, 2017)
  • RAVLT [ Time Frame: Baseline, Week 12 ]
    Change in Rey Auditory Verbal Learning Test (RAVLT)
  • CDR-SOB [ Time Frame: Screening, Baseline, Week 12 ]
    Change in Clinical Dementia Rating Scale - Sum of Boxes (CDR-SOB) and Global (CDR Global)
  • MMSE [ Time Frame: Screening, Baseline, Week 12 ]
    Change in Mini-Mental Status Examination (MMSE)
  • NPI [ Time Frame: Baseline, Week 12 ]
    Change in Neuropsychiatric Inventory (NPI)
  • NTB - Executive Domain [ Time Frame: Baseline, Week 12 ]
    Change in Neuropsychological Test Batteries (NTB) - Executive Domain (COWAT and CFT)
Original Secondary Outcome Measures  ICMJE
 (submitted: March 30, 2016)
  • Rey Auditory Verbal Learning Test (RAVLT) [ Time Frame: Baseline, Week 4, Week 12 ]
  • Clinical Dementia Rating Scale - Sum of Boxes (CDR-SOB) [ Time Frame: Screening, Baseline, Week 4, Week 12 ]
  • Mini-Mental Status Examination (MMSE) [ Time Frame: Screening, Baseline, Week 4, Week 12 ]
  • Neuropsychiatric Inventory (NPI) [ Time Frame: Baseline, Week 12 ]
  • Neuropsychological Test Batteries (NTB) - Executive Domain [ Time Frame: Baseline, Week 12 ]
Current Other Pre-specified Outcome Measures
 (submitted: October 30, 2018)
  • Clinical Safety Laboratory Values [ Time Frame: Screening, Baseline, Week 4, Week 8, Week 12, Week 16 ]
    Change in Clinical Safety Laboratory Values (biochemistry, hematology, urine examination)
  • AEs [ Time Frame: Screening, Baseline, Week 4, Week 8, Week 12, Week 16, Ad Hoc ]
    Incidence of Adverse Events (AEs)
  • ECG [ Time Frame: Screening, Baseline, Week 4, Week 8, Week 12, Week 16 ]
    Change in Electrocardiogram (ECG) Values
  • CSSRS [ Time Frame: Screening, Week 4, Week 8, Week 12, Week 16 ]
    Change in Scores of Columbia Suicide Severity Rating Scale (CSSRS)
  • Metabolic Function [ Time Frame: Baseline, Week 12 ]
    Change in Metabolic Function Test Results of Lipids, Glucose, Hemoglobin A1c (HbA1c)
  • Vital Signs [ Time Frame: Screening, Baseline, Week 4, Week 8, Week 12, Week 16, Unscheduled Safety Visit ]
    Change in Vital Signs (including Heart Rate, Blood Pressure, Body Weight, BMI)
  • NFM [ Time Frame: Screening, Baseline, Week 4, Week 8, Week 12, Week 16 ]
    Change in Nerve Function Monitoring (NFM)
  • NTSS-6 [ Time Frame: Screening, Baseline, Week 4, Week 8, Week 12, Week 16, Ad Hoc and Unscheduled Safety Visit ]
    Change in Neuropathy Total Symptom Score (NTSS-6)
  • PK [ Time Frame: Baseline, Week 4, Week 8, Week 12 and Unscheduled Safety Visit ]
    Change in Pharmacokinetics (PK), including analysis of cortisol levels
  • Optional PD Assessment - Changes in Pharmacodynamic (PD) Measures of Adrenocorticotropic Hormone (ACTH) [ Time Frame: Baseline, Week 4, Week 8, Week 12, Week 16 ]
    This assessment will be carried out on subjects who consented to this optional test. PD sample will be collected at pre-dose at each required visit
  • Optional PD Assessment - Changes in Pharmacodynamic (PD) Measures of Dehydroepiandrosterone Sulfate (DHEAS) [ Time Frame: Baseline, Week 4, Week 8, Week 12, Week 16 ]
    This assessment will be carried out on subjects who consented to this optional test. PD sample will be collected at pre-dose at each required visit
  • Optional PD Assessment - Changes in Pharmacodynamic (PD) Measures of Androstenedione [ Time Frame: Baseline, Week 4, Week 8, Week 12, Week 16 ]
    This assessment will be carried out on subjects who consented to this optional test. PD sample will be collected at pre-dose at each required visit
  • Optional PD Assessment - Changes in Pharmacodynamic (PD) Measures of Testosterone [ Time Frame: Baseline, Week 4, Week 8, Week 12, Week 16 ]
    This assessment will be carried out on subjects who consented to this optional test. PD sample will be collected at pre-dose at each required visit
  • Pregnancy Test [ Time Frame: Screening, Baseline, Week 4, Week 8, Week 12, Week 16 ]
    Women of Childbearing (WOCB) potential only. Serum pregnancy test at Screening and a urine pregnancy test at all subsequent clinic visits.
Original Other Pre-specified Outcome Measures
 (submitted: March 30, 2016)
  • Change in Clinical Safety Laboratory Values (biochemistry, haematology, urine examination) [ Time Frame: Screening, Baseline, Week 4, Week 12, Week 16 ]
  • Incidence of Adverse Events [ Time Frame: Screening, Baseline, Week 4, Week 12, Week 16 ]
  • Change in ECG Values [ Time Frame: Screening, Baseline, Week 4, Week 12, Week 16 ]
  • Changes in the scores of Columbia Suicide Severity Rating Scale (CSSRS) [ Time Frame: Screening, Week 4, Week 12, Week 16 ]
  • Changes in Metabolic function including laboratory results of lipids, glucose, haemoglobin A1c (HbA1c) [ Time Frame: Baseline, Week 4, Week 12 ]
  • Change in Vital Signs (including Heart Rate, Blood Pressure, Body Weight and BMI) [ Time Frame: Screening, Week 4, Week 12, Week 16 ]
  • Optional test - changes in nerve conduction velocity (NCV) [ Time Frame: Baseline, Week 12, Week 24 ]
    This assessment will be carried out on 44 subjects who consent to this optional test.
  • Optional test - change in Pharmacokinetics (PK) parameter Maximum Plasma Concentration (Cmax) [ Time Frame: Baseline, Week 4, Week 12 ]
    This assessment will be carried out on 50 subjects who consent to this optional test at 0 and 3-5 hours post dose
  • Optional test - change in Pharmacokinetics (PK) parameter Time to Cmax (Tmax) [ Time Frame: Baseline, Week 4, Week 12 ]
    This assessment will be carried out on 50 subjects who consent to this optional test at 0 and 3-5 hours post dose
  • Optional test - change in Pharmacokinetics (PK) parameter Area Under the Curve (AUC) [ Time Frame: Baseline, Week 4, Week 12 ]
    This assessment will be carried out on 50 subjects who consent to this optional test at 0 and 3-5 hours post dose
  • Optional test - change in Pharmacokinetics (PK) parameter Terminal Elimination Half Life (t ½) [ Time Frame: Baseline, Week 4, Week 12 ]
    This assessment will be carried out on 50 subjects who consent to this optional test at 0 and 3-5 hours post dose
  • Optional test - change in Pharmacodynamic (PD) measures of adrenocorticotropic hormone (ACTH) [ Time Frame: Baseline, Week 4, Week 12, Week 16 ]
    This assessment will be carried out on 50 subjects who consented to this optional test. PD sample will be collected at pre-dose at each required visit.
  • Optional test - apolipoprotein E (ApoE) genotyping [ Time Frame: Baseline ]
    Detection of ApoE gene in blood sample
  • Optional test - Detection of key biomarkers in Cerebrospinal fluid (CSF) sample [ Time Frame: Baseline, Week 12 ]
    Key biomarkers include phospho-tau, total tau and amyloid-beta-42. CSF samples collected by Lumbar puncture.
  • Optional test - change in Pharmacodynamic (PD) measures of cortisol [ Time Frame: Baseline, Week 4, Week 12, Week 16 ]
    This assessment will be carried out on 50 subjects who consented to this optional test. PD sample will be collected at pre-dose at each required visit.
  • Optional test - changes in Pharmacodynamic (PD) measures of dehydroepiandrosterone sulfate [ Time Frame: Baseline, Week 4, Week 12, Week 16 ]
    This assessment will be carried out on 50 subjects who consented to this optional test. PD sample will be collected at pre-dose at each required visit.
  • Optional test - changes in Pharmacodynamic (PD) measures of androstenedione [ Time Frame: Baseline, Week 4, Week 12, Week 16 ]
    This assessment will be carried out on 50 subjects who consented to this optional test. PD sample will be collected at pre-dose at each required visit.
  • Optional test - changes in Pharmacodynamic (PD) measures of testosterone. [ Time Frame: Baseline, Week 4, Week 12, Week 16 ]
    This assessment will be carried out on 50 subjects who consented to this optional test. PD sample will be collected at pre-dose at each required visit.
 
Descriptive Information
Brief Title  ICMJE A Phase II Study to Assess the Safety, Tolerability and Efficacy of Xanamem™ in Subjects With Mild Dementia Due to AD (XanADu)
Official Title  ICMJE XanADu: A Phase II, Double-Blind, 12-Week, Randomised, Placebo-Controlled Study to Assess the Safety, Tolerability and Efficacy of Xanamem™ in Subjects With Mild Dementia Due to Alzheimer's Disease (AD)
Brief Summary This XanADu Phase II study in mild Alzheimer's Disease (AD) is to assess the safety, tolerability and efficacy of Xanamem™ in subjects with mild dementia due to Alzheimer's Disease. Subjects will be randomized to receive either 10mg once daily Xanamem™ or Placebo at a 1:1 ratio in a double-blinded fashion.
Detailed Description

This is a Phase II, randomised, multi-centre, double-blind, placebo-controlled proof-of-concept study to assess the safety, tolerability and efficacy of oral Xanamem™ once daily in adult subjects with mild dementia due to AD.

Based on Xanamem™'s mode of action on hippocampal function, amnestic symptoms may respond best, thus favouring the inclusion of mild dementia due to AD, with given evidence of disease progression. Subjects will be treated in a double-blind fashion, where both the investigators and subjects will be unaware of the treatment assignments, to minimise any subjective or unrecognised bias carried by the investigators and subjects. Placebo will be used as the comparator in this study.

It is planned to randomise approximately 174 subjects at approximately 25 study sites in three countries (Australia, United Kingdom, and United States), with the aim to enrol 7 to 10 subjects at each study site. Subject enrolment will be competitive but a cap of 20 subjects per study site is to be established to avoid any site effects. In case the sample composition at one study site is creating concerns, an enrolment stop can also occur at fewer than 20 subjects.

The data safety monitoring board (DSMB) will periodically meet for the review of accumulating safety study data and will also be involved in the interim analysis.

At the Baseline visit (Week 0), eligible subjects will be randomised on a 1:1 ratio to receive either Xanamem™ administered orally QD (treatment group) or matching placebo (placebo group). Subjects will return to the study site for visits at Week 4 and Week 8, End of Treatment (Week 12) and Follow-up (4 weeks post last dose of study drug) visits, at which study assessments will be performed.

Ad hoc telephone contact may also occur at any other time-point throughout the study, if deemed necessary by the investigator/study nurse, or if the subject wishes to report an AE.

Subjects will be interviewed and examined at the study site at each visit, and will complete a variety of questionnaires and routine safety evaluations.

Optional PD sampling will be performed at specific visits. Subjects who do not provide consent for this optional sub-study will still be eligible for the main study.

The overall study duration for an individual subject will be 17 to 20 weeks, including a screening period of one to 4 weeks, a double-blind treatment period of 12 weeks, and a follow-up period of 4 weeks. The total duration of the study is expected to be 2 years.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Dementia, Alzheimer Type
Intervention  ICMJE
  • Drug: Xanamem™
    Xanamem™ is formulated in green and cream coloured size 3, Coni-Snap shaped gelatin capsules as an excipient blend at a dose of 10mg. It contains active pharmaceutical ingredient of UE2343
    Other Name: UE2343
  • Drug: Placebo (for Xanamem™)
    Excipient blend capsules manufactured to mimic Xanamem™ capsules
    Other Name: Placebo
Study Arms  ICMJE
  • Experimental: Xanamem™
    Oral Xanamem™ capsules 10mg, to be administered once daily
    Intervention: Drug: Xanamem™
  • Placebo Comparator: Placebo
    Matching placebo which is identical in appearance to the test product except that it contains no active ingredient, to be administered once daily
    Intervention: Drug: Placebo (for Xanamem™)
Publications * Webster SP, McBride A, Binnie M, Sooy K, Seckl JR, Andrew R, Pallin TD, Hunt HJ, Perrior TR, Ruffles VS, Ketelbey JW, Boyd A, Walker BR. Selection and early clinical evaluation of the brain-penetrant 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitor UE2343 (Xanamem™). Br J Pharmacol. 2017 Mar;174(5):396-408. doi: 10.1111/bph.13699. Epub 2017 Jan 25.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: May 8, 2019)
186
Original Estimated Enrollment  ICMJE
 (submitted: March 30, 2016)
200
Actual Study Completion Date  ICMJE March 15, 2019
Actual Primary Completion Date March 15, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Males and females aged 50 years or older at the time of informed consent.
  2. Female Subjects:

    1. Post menopausal women, defined as no menses for 12 months without an alternative medical cause. If there is any concern about the menopausal status of a prospective female subject, a follicle stimulating hormone test (FSH) should be requested to confirm post-menopausal status. Post menopausal women confirmed by FSH level > 40 mIU/mL, will be confirmed by central laboratory.
    2. Women of childbearing potential (WOCBP) must have a negative pregnancy test at Screening and Baseline, and be willing to use highly effective methods of contraception from the Screening visit until 3 months after last dose of study drug. If re-test is required, a local urine pregnancy test will be performed at Baseline to determine if the subject can continue to randomisation.
    3. Are permanently sterile or have had a hysterectomy, bilateral salpingectomy or bilateral oophorectomy.
    4. Women must not be breastfeeding.
  3. Male Subjects:

    1. Who are sexually active, fertile men must use highly effective methods of contraception from Day 1 until 3 months after last dose of study drug if their partners are WOBC.
    2. Who are permanently sterile or have had bilateral orchiectomy.
  4. Diagnosis of mild dementia due to Alzheimer's disease (AD) with increased level of certainty (provided by evidence of clinical deterioration within the 6 months preceding Screening, as assessed by the investigator) as determined by the National Institute of Ageing (NIA) and the Alzheimer's Association (AA) workgroup.
  5. Mild dementia due to probable AD with MMSE 20 to 26 (inclusive).
  6. Clinical Dementia Rating Scale (CDR) Global Score of 0.5 to 1.0.
  7. A brain magnetic resonance imaging (MRI) or computed tomography (CT) scan in the 12 months preceding Screening that in the investigator's opinion is consistent with AD as the principle aetiology of the dementia with no other clinically significant abnormality, e.g. another principle underlying aetiology of the subject's dementia, or a lesion which could affect cognition e.g. a brain tumour or large stroke.
  8. On stable dose of acetylcholinesterase (AChEI) and/or memantine (at least 3 months prior to Screening) OR treatment-naïve. Initiating AChEIs or memantine during the study will not be permitted.
  9. Apart from a clinical diagnosis of mild dementia due to AD, the subject must be in good health as determined by the investigator, based on medical history and screening assessments.
  10. Has a consenting study partner who, in the investigator's judgement, has frequent and sufficient contact with the subject to be able to provide accurate information as to the subject's cognitive and functional abilities. The study partner must be available to provide information to the investigator and study site staff about the subject and agrees to attend all study site visits in person for scale completion. A study partner should be available for the duration of the study. The measure of adequate availability will be at the investigator's discretion.
  11. Must be willing and able to comply with the requirements of the protocol and must be available to complete the study.
  12. Must satisfy a medical examiner about their fitness to participate in the study.
  13. Must provide written informed consent to participate in the study.

Exclusion Criteria:

  1. Clinically significant abnormalities in vital signs (blood pressure, heart rate, respiration rate and oral temperature), as determined by the investigator.
  2. Clinically significant abnormal haematology, biochemistry and urine examination values, specifically abnormal liver and renal function and Vitamin B12 levels below lower threshold since these parameters may impact cognitive function, as determined by the investigator.
  3. Has had a significant systematic illness or infection within the past 4 weeks prior to randomisation, as determined by the investigator.
  4. Clinically significant neurological disease other than AD, such as (but not limited to) Parkinson's disease, multi-infarct dementia, Huntington's disease, normal pressure hydrocephalus, brain tumour, progressive supranuclear palsy, seizure disorder, subdural haematoma, multiple sclerosis or a history of significant head trauma followed by persistent neurologic defaults or known structural brain abnormalities.
  5. Subjects with clinical evidence of peripheral neuropathy or historical evidence of clinically significant nerve conduction abnormalities.
  6. Has had a stroke within the year prior to randomisation, as determined by the investigator.
  7. Has a lifetime diagnosis of a major psychiatric disorder (other than dementia), based on the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition criteria. This includes but is not limited to schizophrenia, schizoaffective disorder, bipolar affective disorder, alcohol dependence syndrome or major depressive disorder.
  8. Has a history of disease directly related to the hypothalamus, the pituitary and/or the adrenal glands which affect the hypothalamic-pituitary-adrenal axis function.
  9. Has uncontrolled clinical conditions relating to glucose and lipid metabolism.
  10. Clinically significant electrocardiogram (ECG) abnormalities, including QTc interval > 450 ms, following ECG tracings at Screening.
  11. Use of any prohibited medication as detailed in the study protocol.
  12. Participation in another clinical study of an investigational drug or device whereby the last investigational drug/device administration is within 60 days of Screening.
  13. Inability to communicate well with the investigator (i.e. language problem, non-fluent English [as scales will be provided in English only], poor mental development or impaired cerebral function).
  14. Subject will undergo the tests, ADAS-Cog v14, CDR-SOB, MMSE, NTB (executive domain) and RAVLT at the indicated time-points to avoid uncontrolled learning effects. Subjects who need to perform these tests externally to and in parallel with this study will be excluded.
  15. Subject has ingested any food or drink containing grapefruit, Seville oranges, star fruit or derived products (e.g. fruit juice), for at least 3 days prior to the first administration of study drug.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 50 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Australia,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02727699
Other Study ID Numbers  ICMJE ACW0002
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party Actinogen Medical
Study Sponsor  ICMJE Actinogen Medical
Collaborators  ICMJE ICON Clinical Research
Investigators  ICMJE
Study Chair: Bill Ketelbey, MD Actinogen Medical
Study Director: Alan Boyd, MD, FFPM Actinogen Medical
PRS Account Actinogen Medical
Verification Date April 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP